Following recognition that intravenous drug users are a high risk group for development of AIDS, it was postulated that heroin could act as a cofactor in the pathogenesis of HIV-1, including development of neuroAIDS, via opiate-mediated immunosuppression and potentiation of viral expression. Despite a large body of supportive evidence, the impact of opiate abuse on HIV-1 pathogenesis remains controversial. Pharmacological considerations have been proposed as one explanation for the conflicting epidemiological and experimental data. The principal hypothesis to be tested in this research proposal is that pharmacologic factors, such as, concentration- and time-dependent responses and interactions with other drugs (i.e., cannabinoids and antiretroviral agents), will markedly influence how morphine, a major metabolite of heroin, and other mu-opioid receptor (MOR) ligands affect two critically important aspects of HIV-1 pathogenesis: 1) viral expression in CD4 and microglial cells, and 2) gp120 protein-induced apoptosis of CD4 and neuronal cells. To test this hypothesis, experiments have been designed that address three specific aims: 1) to investigate the effects of MOR ligands and cannabinoids on HIV-1 expression in CD4 and microglial cell cultures, 2) to investigate whether morphine alters the activity of antiretroviral drugs in these same cell culture models, and 3) to investigate the effects of MOR ligands and cannabinoids on gp120(IIIB)-induced apoptosis of CD4 and neurons. Cannabinoids have been chosen for these studies because of the widespread abuse of the cannabinoid marijuana and a literature demonstrating that cannabinoids also alter the immune system and have interactive effects with opioids. The antiretroviral agents we have chosen for our studies, zidovudine (AZT) and indinavir, are commonly used to treat HIV-1-infected, opiate-dependent patients. The studies designed for this research project promise to provide new insights into the mechanisms whereby opiates and cannabinoids affect the immunopathogenesis and neuropathogenesis of HIV-1 with the long-term goal of developing new approaches to the treatment of the devastating infection caused by this virus.